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Leukocyte Trafficking Via Lymphatic Vessels in Atherosclerosis

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Leukocyte Trafficking Via Lymphatic Vessels in Atherosclerosis cells Review Leukocyte Trafficking via Lymphatic Vessels in Atherosclerosis Kim Pin Yeo, Hwee Ying Lim and Veronique Angeli * Immunology Translational Research Programme, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine and Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore 119077, Singapore; [email protected] (K.P.Y.); [email protected] (H.Y.L.) * Correspondence: [email protected] Abstract: In recent years, lymphatic vessels have received increasing attention and our understanding of their development and functional roles in health and diseases has greatly improved. It has be- come clear that lymphatic vessels are critically involved in acute and chronic inflammation and its resolution by supporting the transport of immune cells, fluid, and macromolecules. As we will dis- cuss in this review, the involvement of lymphatic vessels has been uncovered in atherosclerosis, a chronic inflammatory disease of medium- and large-sized arteries causing deadly cardiovascular complications worldwide. The progression of atherosclerosis is associated with morphological and functional alterations in lymphatic vessels draining the diseased artery. These defects in the lym- phatic vasculature impact the inflammatory response in atherosclerosis by affecting immune cell trafficking, lymphoid neogenesis, and clearance of macromolecules in the arterial wall. Based on these new findings, we propose that targeting lymphatic function could be considered in conjunction with existing drugs as a treatment option for atherosclerosis. Keywords: lymphatic vessel; atherosclerosis; adventitia; lymphangiogenesis; immune cells; choles- terol; inflammation Citation: Yeo, K.P.; Lim, H.Y.; Angeli, V. Leukocyte Trafficking via Lymphatic Vessels in Atherosclerosis. 1. Introduction Cells 2021, 10, 1344. https://doi.org/ The lymphatic system is part of the human circulatory system and the immune 10.3390/cells10061344 system. It is composed of an extensive branched network of lymphatic vessels that are connected to lymph nodes (LNs). Unlike the closed blood circulatory system, lymphatic Academic Editor: Alexander vasculature functions unidirectionally. Extravasated fluid called lymph, macromolecules, E. Kalyuzhny and leukocytes enter the blind-ended initial lymphatic vessels (also called lymphatic capillaries) and are transported towards the pre-collecting vessels that converge to the larger Received: 30 April 2021 collecting vessels, pass through chains of LNs, before returning to the blood circulation Accepted: 26 May 2021 Published: 29 May 2021 through the thoracic duct [1,2]. Lymphatic vessels are present in all vascularized tissues including skin and most internal organs except bone marrow [1]. Hence, each tissue and Publisher’s Note: MDPI stays neutral organ is typically connected to the draining LNs. with regard to jurisdictional claims in Initial lymphatic vessels, the absorptive part of the lymphatic vessels, are lined by a published maps and institutional affil- single layer of oak leaf-shaped lymphatic endothelial cells (LECs) which are not covered by iations. pericytes or smooth muscle cells (SMCs) [3]. Initial lymphatics have discontinuous button- like junctions and are anchored to the extracellular matrix by elastic fibers or anchoring filaments which prevent the vessels from collapsing during high interstitial pressure [4]. These structural features render the initial lymphatics highly permeable, which enables the optimal entry of large macromolecules, pathogens, and immune cells from the interstitial Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. tissues [1]. In contrast, collecting lymphatic vessels exhibit continuous zipper-like cell– This article is an open access article cell junctions, valves, and are ensheathed with a basement membrane and SMCs [4,5]. distributed under the terms and The intrinsic contractility of SMCs and the extrinsic contraction of surrounding skeletal conditions of the Creative Commons muscles and arterial pulsations are necessary for lymph propulsion through the vessel Attribution (CC BY) license (https:// while the valves prevent lymph backflow [6–8]. creativecommons.org/licenses/by/ Lymphatic vessels have been shown to play essential roles in immune surveillance 4.0/). by, for example, supporting antigen and immune cell transport, dietary fat absorption in Cells 2021, 10, 1344. https://doi.org/10.3390/cells10061344 https://www.mdpi.com/journal/cells Cells 2021, 10, 1344 2 of 18 the gastrointestinal tract, and maintenance of tissue fluid balance [1,9–11]. Until recently, the major symptomatic pathological condition associated with defects in lymphatic func- tions was lymphedema. However, lymphatic vessels received increasing attention in the last years and novel, active, and functional roles of the lymphatic vasculature in health and diseases have been discovered. As such, the list of human diseases or disorders associ- ated with defects in lymphatic functions has grown larger and includes Crohn’s disease, neurological disorders, eye diseases such as glaucoma, inflammation, and cardiovascular diseases [12]. In this review, we focus on the functional roles of lymphatic vessels draining medium- and large-sized arteries in atherosclerosis, a chronic inflammatory disease of arteries. We first provide a brief overview of atherosclerosis pathogenesis and then discuss the normal distribution of lymphatic vessels in arteries and their morphological and functional alterations in response to atherosclerosis. Finally, we review recent studies revealing the important contribution of lymphatic vasculature in atherosclerosis progression through the control of immune cell trafficking and lipids. 2. Atherosclerosis: A Chronic Inflammatory Disease of the Arterial Wall 2.1. Intimal Atherosclerotic Plaque Development and Progression Atherosclerosis is a chronic inflammatory disease of medium-sized to large arteries, and the associated cardiovascular complications including myocardial infarction and stroke represent leading causes of death worldwide. The arterial wall consists of three concentric tissue layers namely: the tunica intima (inner layer) lined by a monolayer of endothelial cells, the tunica media composed of SMCs, elastin, and collagen, and the adventitia, the outer layer formed of fibroblasts, collagen, nerve endings, immune cells, and blood and lymphatic vessels (Figure1). Atherosclerosis develops gradually and silently over decades, continuously progressing from early lesions characterized by macrophages loaded with cholesterol ester to advanced lesions with more complex cellular composition, lipid pools, formation of fibrous cap, and necrotic core [13]. According to the traditional inside-out theory of atherosclerotic lesion development, the disease is initiated from the luminal side of the artery and involves several orchestrated mechanisms triggered by endothelial activation and subendothelial retention of plasma apolipoprotein in the intima, including monocyte adhesion on the luminal surface, en- dothelial dysfunction, leukocyte accumulation in the subendothelial space, and subsequent inflammatory responses [14,15]. The extracellular modifications of lipoproteins such as oxidation induce the local innate and adaptive immune responses in the intima through the activation of inflammatory cells, which in turn respond by producing pro-inflammatory cy- tokines and chemokines [16]. The latter promote further recruitment of various circulating leukocytes and local activation of endothelial cells. The inflammatory cells that infiltrate the developing atherosclerotic lesions include monocytes and monocyte-derived macrophages, dendritic cells, various subsets of T and B lymphocytes, mast cells, and, in the more ad- vanced, often thrombotic lesions, neutrophils [17–25]. The intimal monocyte-derived cells also contribute to the modification of the apolipoprotein B-containing lipoproteins through the secretion of lipoprotein-modifying enzymes or agents [26–28]. Uptake of modified lipoproteins or of cholesterol crystals by macrophages, dendritic cells, and vascular SMC leads to the accumulation of cytoplasmic cholesteryl ester droplets leading to the formation of “foamy” cells, a histological hallmark of atherogenesis. Since excess of un-esterified or free cholesterol is toxic to cells, foam cell formation involving esterification and storage of cholesterol as cholesteryl ester droplets can be considered as a beneficial process in the early atherosclerotic lesions. During disease progression, continuous recruitment of monocytes, deposition of cholesterol crystals, migration of medial SMCs to the intima, and undesirable immunity against cholesterol-associated apolipoproteins trigger and sustain chronic inflam- mation. In advanced lesions, foams cells die and release their contents into the extracellular microenvironment and contribute further to inflammation, formation of lipid-rich necrotic core, and plaque instability. Unstable plaques are also characterized by the thinning of Cells 2021, 10, x FOR PEER REVIEW 4 of 20 erosclerotic plaques. Adventitial mononuclear cell infiltration associated with human ath- eromatous plaques was reported in coronary arteries by Gerlis in 1956 [43] and by Schwartz and Mitchell in 1962 [44]. A similar adventitial response was further docu- mented in the human aorta by Parums and Ramshaw [45]. In the atherosclerotic mouse model lacking apolipoprotein E (Apoe−/−), the number of macrophages, T cells, and mi- crovessels was significantly higher in
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